Method of manufacturing of 7-ethyl-10-hydroxycamptothecin

ABSTRACT

The method of manufacturing of 7-ethyl-10-hydroxycamptothecin of formula I characterized in that 7-ethyl-1,2,6,7-tetrahydrocampotothecin of formula IV is oxidized with an oxidizing agent selected from the group comprising iodosobenzene, an ester of iodosobenzene, sodium periodate, potassium periodate, potassium peroxodisulfate and ammonium peroxodisulfate, in a solvent formed by a saturated aliphatic monocarboxylic add containing 1 to 3 carbon atoms, and in the presence of water.

FIELD OF THE INVENTION

This invention relates to the method of manufacturing of7-ethyl-10-hydroxycamptothecin of formula I

which is used for manufacturing of cytostatically active irinotecanhydrochloride trihydrate, effective particularly in treatment of lungand rectum cancer. The cytostatic effect of irinotecan hydrochloridetrihydrate is based on its ability to inhibit topoisomerase.

BACKGROUND OF THE INVENTION

So far, 7-ethyl-10-hydroxycamptothecin is usually prepared in tworeaction steps. In the first reaction step, 7-ethylcamptothecin offormula II

is oxidized with hydrogen peroxide in acetic acid under formation of7-ethylcamptothecin 1-oxide of formula III

which in the second reaction step is dissolved-in the solvent systemdioxane-acetonitrile-water and the solution is irradiated with UV lightin the presence of sulfuric acid to afford the desired7-ethyl-10-hydroxycamptothecin (see U.S. Pat. No. 4,473,692 and U.S.Pat. No. 4,513,138 and Zhongguo Yaowu Huaxue Zazhi 2001, 11 (4),238-240).

However, this method of manufacturing of 7-ethyl-10-hydroxycamptothecinsuffers from the fact that the oxidation of 7-ethylcamptothecin in thefirst reaction step requires relatively great amount of acetic acid (300ml of acetic acid per 1 gram of 7-ethylcamptothecin). In the isolationof the obtained 7-ethylcamptothecin 1-oxide it is necessary to evaporateone fourth of the acetic acid volume, add water to the evaporationresidue and subsequently collect the precipitated 7-ethylcamptothecin1-oxide by filtration. This isolation procedure is demanding and affectsvery unfavourably the yield of 7-ethylcamptothecin 1-oxide. In thesecond step, the isolation of 7-ethyl-10-hydroxycamptothecin, consistsin removal of the solvent mixture by distillation, dilution with water,extraction with chloroform and drying the chloroform layer overmagnesium sulfate, followed by purification on a silica gel column withthe aim to remove impurities arising in the UV irradiation. In spite ofthis complicated isolation procedure, the obtained7-ethyl-10-hydroxycamptothecin still contains up to 22% by weight of7-ethylcamptothecin. In this method the total yield of both reactionsteps is only about 38%.

The aim of the invention is to find a less demanding method of producing7-ethyl-10-hydroxycamptothecin that would afford7-ethyl-10-hydroxycamptothecin in higher yields and higher purity. Thisaim has been achieved by the method according to the present invention.

SUMMARY OF THE INVENTION

The present invention relates to the method of manufacturing of7-ethyl-10-hydroxycamptothecin of formula I

which is characterized in that 7-ethyl-1,2,6,7-tetrahydrocamptothecin offormula IV

is oxidized with an oxidizing agent selected from the group comprisingiodosobenzene, an ester of iodosobenzene, sodium periodate, potassiumperiodate, potassium peroxodisulfate and ammonium peroxodisulfate, inthe presence of a solvent formed by a saturated aliphatic monocarboxylicacid comprising 1 to 3 carbon atoms, and in the presence of water.

The oxidizing agent is preferably an ester of iodosobenzene, morepreferably an ester of iodosobenzene of general formula V

in which substituents R¹ are the same or different and designatehydrogen, —C(O)—R² or —SO₂—R³ where R² and R³ independently are selectedfrom a group comprising an optionally substituted alkyl group having 1to 6 carbon atoms, an optionally substituted cycloalkyl group having 3to 8 carbon atoms, an optionally substituted aryl group having 6 to 12carbon atoms, and an optionally substituted aralkyl group in which thearyl moiety has 6 to 12 carbon atoms and the alkyl moiety has 1 to 4carbon atoms, with the proviso that at least one of the substituents R¹is not the hydrogen atom, in particular an ester of iodosobenzeneselected from a group comprising iodobenzene diacetate, iodobenzenebis(trifluoroacetate) and hydroxy(tosyloxy)iodobenzene. Iodobenzenediacetate is advantageously used in an amount of 0.99 to 1.85 mol, moreadvantageously 1.28 to 1.56 mol, per 1 mol of7-ethyl-1,2,6,7-tetrahydrocamptothecin.

Suitable solvents include acetic acid, formic acid or trifluoroaceticacid. Preference is given to acetic acid in amounts from 668 to 1001mol, more preferably 751 to 918 mol, per 1 mol of7-ethyl-1,2,6,7-tetrahydrocamptothecin.

Water is advantageously used in amounts from 0.98 to 1.88 mol,preferably from 1.28 to 1.58 mol, per 1 mol of7-ethyl-1,2,6,7-tetrahydrocamptothecin.

The oxidation is carried out preferably at a temperature in the range of15 to 30° C., more preferably at 18 to 25° C., the reaction time being 5to 30 minutes, more preferably 10 to 15 minutes.

The starting 7-ethyl-1,2,6,7-tetrahydrocamptothecin is preferablyobtained by hydrogenation of 7-ethylcamptothecin of formula II

in a saturated aliphatic monocarboxylic acid having 1 to 3 carbon atoms,using hydrogen in the presence of a hydrogenation catalyst and a sulfurcompound partly deactivating the hydrogenation catalyst.

Preferred saturated aliphatic monocarboxylic acids are formic acid,acetic acid or trifluoroacetic acid, more preferred being acetic acid inan amount of 791 to 1187 mol, most preferably 890 to 1088 mol, per 1 molof 1-ethylcamptothecin.

Preferred sulfur compound that partly deactivates the hydrogenationcatalyst is dimethyl sulfoxide, preferably in an amount of 0.18 to 0.33mol, more preferably in an amount of 0.23 to 0.28 mol, per 1 mol of7-ethylcamptothecin.

Preferred hydrogenation catalyst is a noble metal, preferably platinumwhich is advantageously used on a carrier consisting of an activatedcarbon or aluminum oxide. Platinum is advantageously used in an amountof 0.018 to 0.027 mol, more advantageously in an amount of 0.020 to0.025 mol, per 1 mol of 7-ethylcamptothecin, in the form ofhydrogenation catalyst consisting of platinum on an activated carbonwith platinum content of 5%. The hydrogenation is performedadvantageously at a pressure from 0.3 to 0.7 MPa, more preferably at 0.4to 0.6 MPa, at a temperature from 45 to 85° C., more preferably at 58 to72° C., for 24 to 70 hours, more preferably for 40 to 50 hours.

After the end of the oxidation, undesired compounds are removed in thefollowing way. The solvent is distilled off,7-ethyl-10-hydroxycamptothecin is precipitated in acetonitrile andisolated by filtration and washing with acetonitrile. In the procedureaccording to the present invention, at least 58% yield of7-ethyl-10-hydroxycamptothecin is achieved in a relative purity of 90%,as determined by high performance liquid chromatography.

A substantial advantage of the method according to this invention overthe prior art ones is that in the oxidation of7-ethyl-1,2,6,7-tetrahydrocamptothecin no coloured side products areformed that need be removed by chromatography on a silica gel column. Inan advantageous embodiment of this invention, the oxidation is precededby hydrogenation of 7-ethylcamptothecin under formation of7-ethyl-1,2,6,7-tetrahydrocamptothecin which advantageously is notisolated, the oxidation being performed directly with the obtainedhydrogenation mixture from which only the hydrogenation catalyst hasbeen removed.

In the following example, the method according to this invention isdescribed in more detail, this example being for illustration only,without limiting in any way the scope of the invention which isunequivocally defined by the patent claims and the description part.

EXAMPLES Example 1

In a 100 ml beaker, 0.5 g (1.239 mmol) of 7-ethylcamptothecin, 0.32 g of5% hydrogenation catalyst Pt/C (containing 0.028 mmol of platinum) and0.025 ml (0.352 mmol) of dimethyl sulfoxide are added to 70 ml of aceticacid. The obtained suspension is quantitatively transferred into a 100ml autoclave. After closure, the autoclave is flushed three times withnitrogen at the pressure of 0.5 MPa and then three times with hydrogenat the pressure of 0.5 MPa. The temperature is adjusted to 65° C. andthe mixture is stirred at 950 r.p.m. The hydrogen pressure is adjustedto 0.5 MPa. After 43.5 hours the consumption of hydrogen stops and theprocedure is terminated. After cooling to 25° C., the stirring isstopped and the internal pressure is equilibrated with the ambientatmosphere. The autoclave is flushed three times with nitrogen, thehydrogenation catalyst is removed from the hydrogenation mixture byfiltration under pressure of nitrogen and the catalyst cake is washedwith 10 ml of acetic acid. The obtained solution (80 ml) of7-ethyl-1,2,6,7-tetrahydrocamptothecin is immediately added undervigorous stirring into a 250 ml one-necked flask containing 22 ml (1.218mol) of water and 0.77 g (2.343 mmol) of iodobenzene diacetate. Theobtained solution is stirred for 15 minutes at 22° C. Then the solventis evaporated and the residue is mixed with 10 ml of acetonitrile. Theobtained suspension is homogenized by sonication. The solid7-ethyl-10-hydroxycamptothecin is isolated by filtration, washed on thefilter with 10 ml of acetonitrile and dried to the constant weight in avacuum oven at 60° C. to 65° C. The yield of7-ethyl-10-hydroxycamptothecin is 0.283 g (58.3%). Its relative purity,determined by high performance liquid chromatography, is 90.2%.

1. A process for the preparation of 7-ethyl-10-hydroxycamptathecin offormula I

comprising oxidizing 7-ethyl-1,2,6,7-tetrahydrocamptothecin of formulaIV

with an oxidizing agent selected from the group comprisingiodosobenzene, an ester of iodosobenzene, sodium periodate, potassiumperiodate, potassium peroxodisulfate and ammonium peroxodisulfate, in asolvent formed by a saturated aliphatic monocarboxylic acid containing 1to 3 carbon atoms, and in the presence of water, wherein the water isused in an amount of 0.98 to 1.88 mol per 1 mol of7-ethyl-1,2,6,7-tetrahydrocamptothecin.
 2. The process according toclaim 1, wherein the oxidizing agent is an ester of iodosobenzene. 3.The process according to claim 2, wherein the ester of iodosobenzene isan ester of iodosobenzene of general formula V

wherein substituents R¹ are the same or different and are selected fromhydrogen, —C(O)—R² and —SO₂—R³, where R² and R³ are independentlyselected from a group comprising an optionally substituted alkyl grouphaving 1 to 6 carbon atoms, an optionally substituted cycloalkyl grouphaving 3 to 8 carbon atoms, an optionally substituted aryl group having6 to 12 carbon atoms, and an optionally substituted aralkyl groupwherein the aryl moiety has 6 to 12 carbon atoms and the alkyl moietyhas 1 to 4 carbon atoms, with the proviso that at least one of thesubstituents R¹ is not the hydrogen atom.
 4. The process according toany one of claims 1 to 3, wherein the oxidizing agent is an ester ofiodosobenzene selected from iodobenzene diacetate, iodobenzenebis(trifluoroacetate) and hydroxy(tosyloxy)iodobenzene.
 5. The processaccording to claim 4, wherein the oxidizing reagent is iodobenzenediacetate in an amount of 0.99 to 1.85 mol, per 1 mol of7-ethyl-1,2,6,7-tetrahydrocamptothecin.
 6. The process according toclaim 1, wherein the solvent is acetic acid, formic acid ortrifluoroacetic acid.
 7. The process according to claim 6, wherein thesolvent is acetic acid in an amount of 668 to 1001 mol per 1 mol of7-ethyl-1,2,6,7-tetrahydrocamptothecin.
 8. The process according toclaim 7, wherein water is used in an amount of 1.28 to 1.58 mol per 1mol of 7-ethyl-1,2,6,7-tetrahydrocamptothecin.
 9. The process accordingto claim 1, wherein the oxidation is carried out at a temperature from15 to 30° C.
 10. The process according to claim 1, wherein the oxidationis performed for 5 to 30 minutes.
 11. The process according to claim 1,wherein the starting 7-ethyl-1,2,6,7-tetrahydrocamptothecin is obtainedby hydrogenation of 7-ethylcamptothecin of formula II

in a saturated aliphatic monocarboxylic acid having 1 to 3 carbon atoms,using hydrogen in the presence of a hydrogenation catalyst and a sulfurcompound that partly deactivates the hydrogenation catalyst.
 12. Theprocess according to claim 11, wherein the saturated aliphaticmonocarboxylic acid is formic acid, acetic acid or trifluoroacetic acid.13. The process according to claim 12, wherein acetic acid is used in anamount of 791 to 1187 mol per 1 mol of 7-ethylcamptothecin.
 14. Theprocess according to claim 11, wherein the sulfur compound that partlydeactivates the hydrogenation catalyst is dimethyl sulfoxide.
 15. Theprocess according to claim 14, wherein dimethyl sulfoxide is used in anamount of 0.18 to 0.33 mol per 1 mol of 7-ethylcamptothecin.
 16. Theprocess according to claim 11, wherein the hydrogenation catalyst is anoble metal.
 17. The process according to claim 16, wherein the noblemetal is platinum.
 18. The process according to claim 17, whereinplatinum is used on an activated carbon or aluminum oxide carrier. 19.The process according to claim 18, wherein platinum is used in an amountof 0.018 to 0.027 mol per 1 mol of 7-ethylcamptothecin, in the form of ahydrogenation catalyst, formed by platinum on an activated carbon withplatinum content 5%.
 20. The process according to claim 11, wherein thehydrogenation is carried out at a pressure from 0.3 to 0.7 MPa.